There are many situations in which one needs to monitor for the presence of minute quantities of chemical species highly diluted in very complex mixtures. One class of examples is provided in drug development and medical diagnosis, where body fluids (blood, plasma, urine, breath, etc.) are monitored for the presence of certain key metabolites. Another example is given in civilian and military security, or in law enforcement applications, when one wishes to probe for the presence of extremely dilute volatile species in the atmosphere, where many thousands of other similar species naturally exist in comparable or much higher concentrations. In situations where one seeks to establish whether one or several target ions of specific interest are present or absent above a certain threshold, it is possible to avoid a complete analysis and search only for the desired target species in so called single ion monitoring mode (SIM). This mode is best achieved by use of analytical instruments acting as narrow band filters, which block the passage of most species, allowing through only specific ones having certain characteristics (say mass over charge, electrical mobility, etc., which we shall for convenience denote as the filtering parameters) very close to certain set values. One example of such narrow band filter is the quadrupole mass spectrometer, for which the filtering parameter is the mass over charge ratio of an ion. Another example is a differential mobility analyzer, for which the filtering parameter is the electrical mobility of an ion. The triple quadrupole mass spectrometer (3QMS) with an atmospheric pressure ionization source (API) is in fact one of the preferred instruments used in pharmaceutical applications for such monitoring (note however that the tern atmospheric is part of a generic denomination and does not necessarily imply that it is restricted to operate under atmospheric pressure. Nor does the use of generic atmospheric pressure ionization mass spectrometers made in this invention restrict the invention to atmospheric conditions). It is often coupled with prior separation stages, such as liquid chromatography (LC, which separates dissolved species in the liquid phase), ion mobility spectrometry (IMS, which separates ions in the gas phase; see Eiceman and Karpas, 1994), etc. The triple quadrupole acts in a first stage as an ion filter allowing passage only of a narrow range of ions with fixed mass/charge ratio (m/z), then produces fragments of these species by impact with neutral gas molecules in a second stage, and analyzes finally the daughter products or fragment ions of such collisions in a third stage. The complex signature of the mass of a parent ion combined with the masses of its generally very specific fragmentation (daughter) ions is generally highly discriminating. Much greater specificity is added by LC, but this stage is rather slow compared with MS separation. Excellent additional fast discrimination has been achieved by adding IMS separation. However, conventional IMS separates ions in time, while a quadrupole mass spectrometer does so in space, whereby the combination IMS-MS is not ideal for use with quadrupoles, particularly in single ion monitoring mode (SIM). IMS-MS has nonetheless been developed into an effective technique (principally by D. Clemmer and colleagues; see Counterman et al., 2001) in combination with time of flight mass spectrometers (TOF-MS), and provides a very useful tool for complete two-dimensional mapping of mobility and mass distributions of complex mixtures. However, when the task at hand is to monitor for a discrete number of expected target ions, the quadrupole MS is considerably more effective. This has led to the development of ion mobility separation schemes where separation takes place in space rather than in time. For instance, so-called Field Asymmetric IMS (FAIMS) does just that. FAIMS has recently been developed from its Russian origins by Dr. Roger Guevremont (see for instance U.S. Pat. Nos. 6,639,212 and 6,774,360), and exists commercially coupled to triple quadrupole mass spectrometers. Although FAIMS has a relatively modest resolving power (R˜15), it is claimed to be fairly effective in reducing chemical noise. Other even more sophisticated devices have been demonstrated, combining FAIMS, conventional IMS and MS to achieve a very high global discrimination power. However, the coupling of IMS with a quadrupole MS remains as inefficient in these triple combinations as in IMS-MS. In spite of their many advantages, triple quadrupole instruments are generally relatively heavy (>100 kg) and expensive (<$200,000), and this has limited their use in certain applications. In particular, for the purpose of screening for explosives and other illegal substances, there is a need for relatively portable instruments, which has led to the wide use of IMS in airports and other security check points. IMS, however, is much less discriminating and sensitive than API-MS, and is therefore subject to two kinds of drawbacks. First, its limited sensitivity makes it impossible to sense low vapor pressure explosives in the gas phase, demanding instead slower concentration protocols. Second, IMS's limited resolution leads to a relatively high probability of false alarms, particularly when dealing with low vapor pressure substances for which very many other background vapors exist in comparable or larger concentrations. The difficulty is readily seen through the following example. The electrical mobilities Z in ambient air for most volatile species range between 1.5 and 2 cm2/V/s. The best IMS instruments available are able to resolve species whose mobilities differ by 1%. This means that an IMS system can only distinguish 29 different peaks in this relevant mobility range (1.0129˜2/1.5). In cases where more such species are present, they cannot be resolved from each other, and cannot therefore be unambiguously identified. Even worse, since the number of sufficiently volatile chemicals of interest in applications such as medical diagnostics, security, analytical, etc., include many tens of thousands, many of them can have electrical mobilities differing from each other by less than 1%. The result is that, when monitorin(g for a dangerous or desired substance in an IMS system at a particular electrical mobility, the appearance of a clear signal is generally associated not to the species searched for, but to one of the many others having very close mobilities. This is the well-known problem of the false positives. Its seriousness is evident from the gravity of its consequences. For instance, airports have as a result been shut down for hours leading to vast economic losses. In combat, a false alarm may force soldiers to equip themselves with masks and other heavy and inconvenient gear, leading to a serious loss of effectiveness.
There is therefore a need for reasonably portable analytical instruments with much higher discrimination power and sensitivity than IMS. One possible solution could conceivably be based on U.S. Pat. No. 5,869,831, where a differential mobility analyzer (DMA) is combined in series with a mass spectrometer. The DMA discriminates various ions according to their electrical mobility Z, similarly as conventional IMS. However, it separates ions in space rather than in time by combining an electric field and the flow field of a gas, generally air, as described in U.S. Pat. Nos. 5,869,831 and 5,936,242, and more generally in U.S. Pat. No. 6,787,763, and in US Patent Application 20070272847. For present purposes, we will define a DMA generally as a device separating ions in space by combining an electric field and the flow field of a gas. In order to clearly distinguish DMAs from FAIMS instruments, we add the restriction that the flow velocity in the separation region of the DMA must be comparable to the maximum instantaneous ion velocity drift caused by the electric field. More precisely, while the flow velocity can be much smaller than this maximum ionic electrical drift velocity in FAIMS devices, it is typically larger than ½ of the ion drift velocity in DMAs. DMAs can act as narrow band ion filters, taking at their ion inlet a multitude of ions with many different mobilities, and delivering at their ion outlet only those ions having a specified electrical mobility ZO. This ZO is controllable through either the flow rate of gas circulating through the DMA, or the voltage difference between two or more DMA electrodes or grids. The later parameters are generally referred as the classification voltages, or the classification voltage when only one voltage is controlled. In what follows, without loss of generality, we shall for simplicity refer to just one classification voltage. The fact that both the DMA and the quadrupole mass spectrometer are narrow band ion filters, and the fact that the mobility-classified ions exiting the ion outlet of the DMA can be introduced into the sample inlet of the mass spectrometer permits the series operation of both filters in what we shall refer to as a tandem connection, or a coupling in series. The same coupling is possible between a DMA and other MS types. Because FAIMS constitutes also a band-pass ion filter, it can be similarly coupled to various MS types.
Many other embodiments of the principle of separation of ions in space by combining electric and fluid flow fields have been described in the literature, as reviewed in a book by H. Tammet (1970), and as discussed in US patent application 20070272847.
The DMA-MS arrangement does greatly increase the discrimination power of the MS without loss of its sensitivity to the particular mobility passed. However, the DMA is a scanning instrument, and this combination has to date been used in a mode where both the DMA and the MS were scanned, whereby the limited signal available is less efficiently used than in the IMS-TOF approach of Clemmer and colleagues. Scanning DMA-MS analyses are therefore time consuming, and incompatible with many of the security monitoring tasks previously alluded. Furthermore, use of the high discrimination potential offered by tandem mass spectrometers is available to the DMA-MS combination only when the DMA is attached to a relatively expensive and heavy tandem MS. In order to resolve these various problems, the present invention includes first a method to control a DMA combined with a relatively light and economical single stage quadrupole MS (IQMS), such that a large number of ions can be monitored in so called single ion monitoring (SIM) mode, at essentially the same speed as with MS alone, but with the much greater discrimination power offered by a DMA-MS combination. This first method then overcomes the prior slowness of DMA-MS operation, enhances the resolution of pure MS, and also increases the signal/noise ratio of pure MS. The invention includes also a second method to control a DMA-IQMS combination such as to obtain much higher discrimination powers, comparable to those offered by the ion fragmentation patterns available in tandem mass spectrometry. A third combination taught in this invention relies on two or more DMAs in series, which may be used with or without a mass spectrometer. In order for the two DMA separations to be different from each other, at least one of the two DMAs is operated in a regime of high drift speed, where the ion mobility depends on the intensity of the field.